Intraluminal electrode apparatus and method

ABSTRACT

At least one of a plurality of disorders of a patient associated with vagal activity innervating at least one of a plurality of organs of the patient at an innervation site are treated by positioning a neurostimulator carrier within a body lumen of the patient. An electrode disposed on the carrier is positioned at a mucosal layer of the lumen. An electrical signal is applied to the electrode to modulate vagal activity by an amount selected to treat the disorder. The signal may be a blocking or a stimulation signal.

I. CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application is a continuation-in-part application ofthe following U.S. patent applications, all filed on Sep. 29, 2003: U.S.patent application Ser. No. 10/674,330, entitled “Nerve Conduction BlockTreatment”; U.S. patent application Ser. No. 10/675,818, entitled“Enteric Rhythm Management” and U.S. patent application Ser. No.10/674,324, entitled “Nerve Stimulation And Conduction Block Therapy”.The afore-mentioned patent applications are continuation-in-partapplications of U.S. patent application Ser. No. 10/358,093 filed Feb.3, 2003 and entitled “Method and Apparatus for Treatment ofGastroesophageal Disease (GERD)”. The present application also claimspriority to the afore-said Ser. No. 10/358,093. The present applicationdiscloses and claims subject matter disclosed in the following commonlyassigned and copending U.S. patent applications filed on the same dateas the present application and in the name of the same inventors: U.S.patent application Ser. No. not yet assigned, entitled “Electrode BandApparatus And Method”, having Attorney Docket No. 14283.1US14.

II. BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] This invention pertains to treatments of disorders associated, atleast in part, with neural activity. These may include, withoutlimitation, gastrointestinal, pancreo-biliary, cardio-respiratory andcentral nervous system disorders (including neurological andpsychiatric, psychological and panic disorders). More particularly, thisinvention pertains to treatment of such disorders through management ofneural impulse stimulation and blocking.

[0004] 2. Description of the Prior Art

[0005] A. Functional Gastrointestinal Disorders (FGIDs)

[0006] Functional Gastrointestinal Disorders (FGIDS) are a diagnosticgrouping having diagnostic criteria based on symptomatology, because thepathophysiology of these diseases is multifactorial with somepathophysiologic mechanisms in common. FGIDs are thought to be due toaltered autonomic nervous system balance and to be pathophysiologicalcombinations of: (1) abnormal GI motility; (2) visceralhypersensitivity; and, (3) brain-gut interactions. Tougas, “TheAutonomic Nervous System in Functional Bowel Disorders”, Gut, Vol. 47(Suppl IV), pp. iv78-iv80 (2000) and Drossman, “Rome II: A MultinationalConsensus Document on Gastrointestinal Disorders—The FunctionalGastrointestinal Disorders and the Rome II Process”, Gut, Vol. 45 (SupplII):II1-II5 (1999). The FGIDs of interest to the present invention arefunctional dyspepsia (dysmotility-like) and irritable bowel syndrome(IBS).

[0007] 1. Functional Dyspepsia (Dysmotility-Like)

[0008] Functional dyspepsia (dysmotility-like), is diagnosed when apatient's symptoms, in the absence of other organic disease likely toexplain the symptoms, include persistent or recurrent pain or discomfortcentered in the upper abdomen that may be accompanied by upper abdominalfullness, early satiety, bloating or nausea. Talley et al., “Rome II: AMultinational Consensus Document on GastrointestinalDisorders—Functional Gastroduodenal Disorders” Gut, Vol. 45 (Suppl II),pp. I37-II42 (1999).

[0009] A spectrum of dysmotilities has been documented in patients withfunctional dyspepsia. These include delayed gastric emptying of solidsand liquids, reduced vagal tone, gastric dysrhythmias and impairedgastric accommodation. Furthermore, some studies have found goodcorrelation between symptoms and indices of dysmotility, while othershave not. Stanghellini V, et al., “Delayed Gastric Emptying of Solids inPatients with Functional Dyspepsia”, Gastroenterol, (1996)110:1036-1042. Undeland K A, et al., “Wide Gastric Antrum and Low VagalTone in Patients with Diabetes Mellitus Type 1 Compared to Patients withFunctional Dyspepsia and Healthy Individuals”, Dig Dis Sci, (1996)41:9-16. Tack J, et al., “Role of Inpaired Gastric Accommodation to aMeal in Functional Dyspepsia”, Gastroenterol, (1998) 115:1346-1352.Wilmer A, et al., “Ambulatory Gastrojejunal Manometry in SevereMotility-like Dyspepsia: Lack of Correlation between Dysmotility,Symptoms and Gastric Emptying”, Gut, (1998) 42:235-242. Tack J, et al.,“Symptom Pattern and Gastric Emptying Rate Assessed by the Octanoic AcidBreath Test in Functional Dyspepsia” [abstract]. Gastroenterol, (1998)114:A301. Cuomo R, et al., “Functional Dyspepsia Symptoms, GastricEmptying and Satiety Provocation Test: Analysis of Relationships”, ScandJ Gastroenterol, (2001) 36:1030-1036. Sarnelli G, et al., “SymptomsAssociated with Impaired Gastric Emptying of Solids and Liquids inFunctional Dyspepsia”, Am J Gastroenterol, (2003) 98:783-788.

[0010] 2. Irritable Bowel Syndrome (IBS)

[0011] The second FGID of interest, IBS, is diagnosed when a patient'ssymptoms include persistent abdominal pain or discomfort, in the absenceof other explanatory organic disease, along with at least two of thefollowing: relief of pain with defecation, onset of symptoms associatedwith a change in frequency of stools and/or onset of symptoms associatedwith a change in appearance/form of stools. Thompson W G, et al., “RomeII: A Multinational Consensus Document on GastrointestinalDisorders—Functional Bowel Disorders and Functional Abdominal Pain”,Gut, (1999);45(Suppl II):II43-II47.

[0012] In addition to colonic dysmotility, a number of other GI motilityabnormalities have been identified, including delayed gastric emptying,gastroparesis, and small intestine motility abnormalities. Vassallo M J,et al., “Colonic Tone and Motility in Patients with Irritable BowelSyndrome”, Mayo Clin Proc, (1992);67:725-731. Van Wijk H J, et al.,“Gastric Emptying and Dyspeptic Symptoms in the Irritable BowelSyndrome”, Scand J Gastroenterol, (1992);27:99-102. Evans P R, et al.,“Gastroparesis and Small Bowel Dysmotility in Irritable Bowel Syndrome”,Dig Dis Sci (1997);42:2087-2093. Cann P A, et al. “Irritable BowelSyndrome: Relationship of Disorders in the Transit of a Single SolidMeal to Symptoms Patterns”, Gut, (1983);24:405-411. Kellow J E, et al.,“Dysmotility of the Small Intestine in Irritable Bowel Syndrome”, Gut,(1988);29:1236-1243. Evans P R, et al., “Jejunal SensorimotorDysfunction in Irritable Bowel Syndrome: Clinical and PsychosocialFeatures”, Gastroenterol, (1996);110:393-404. Schmidt T, et al.,“Ambulatory 24-Hour Jejunal Motility in Diarrhea-Predominant IrritableBowel Syndrome”, J Gastroenterol, (1996);31:581-589. Simren M, et al.,“Abnormal Propagation Pattern of Duodenal Pressure Waves in theIrritable Bowel Syndrome (IBS)”, Dig Dis Sci, (2000);45:2151-2161.

[0013] A related finding is that patients with constipation-predominantIBS have evidence of decreased vagal tone, while diarrhea-predominantIBS is associated with evidence of increased sympathetic activity.Aggarwal A, et al., “Predominant Symptoms in Irritable Bowel SyndromeCorrelate with Specific Autonomic Nervous system Abnormalities”,Gastroenterol,(1994);106:945-950.

[0014] There is no cure for IBS. Treatments include supportivepalliative care (antidiarrheals, dietary modification and counseling).

[0015] A recently approved drug to treat selected patients with FGIDs istegaserod maleate sold under the tradename “Zelnorm®” by NovartisPharmaceuticals Corp., East Hanover, N.J., USA. The product literatureon Zelnorm recognizes the enteric nervous system is a key element intreating IBS. The literature suggests Zelnorm® acts to enhance basalmotor activity and to normalize impaired motility. Novartis productdescription, Zelnorm®, July 2002 (T2002-19). Zelnorm's approved use islimited to females with constipation-related IBS. It is for short-termuse only.

[0016] B. Gastroparesis

[0017] The third disease indication discussed here, gastroparesis (ordelayed gastric emptying) is associated with upper GI symptoms such asnausea, vomiting fullness, bloating and early satiety. Gastroparesis canbe caused by many underlying conditions. The most important, because ofchronicity and prevalence, are diabetes, idiopathic and post-surgical.Hombuckle K, et al. “The Diagnosis and Work-Up of the Patient withGastroparesis”, J Clin Gastroenterol, (2000);30:117-124. GI dysmotilityin the form of delayed gastric emptying is, by definition, present inthese patients.

[0018] In patients with Type 1 diabetes mellitus and delayed gastricemptying, there appears to be a relationship between delayed gastricemptying and low vagal tone. Merio R, et al., “Slow Gastric Emptying inType 1 Diabetes: Relation to Autonomic and Peripheral Neuropathy, BloodGlucose, and Glycemic Control”, Diabetes Care, (1997);20:419-423. Arelated finding is that patients with Type 1 diabetes have low vagaltone in association with increased gastric antral size, possiblycontributing to the dysmotility-associated symptoms seen in thesepatients. Undeland K A, et al., “Wide Gastric Antrum and Low Vagal Tonein Patients with Diabetes Mellitus Type 1 Compared to Patients withFunctional Dyspepsia and Healthy Individuals”, Dig Dis Sci,(1996);41:9-16.

[0019] The current treatments for gastroparesis are far fromsatisfactory. They include supportive care, such as dietarymodification, prokinetic drugs, and; when required, interventions suchas intravenous fluids and placement of a nasogastric tube may be needed.

[0020] C. Gastroesophageal Reflux Disease (GERD)

[0021] The fourth indication, GERD, can be associated with a widespectrum of symptoms, including dyspepsia, reflux of gastric contentsinto the mouth, dysphagia, persistent cough, refractory hyperreactiveairway disease and even chronic serous otitis media. Sontag S J, et al.,“Asthmatics with Gastroesophageal Reflux: Long Term Results of aRandomized Trial of Medical and Surgical Antireflux Therapies”, Am JGastroenterol, (2003);98:987-999. Poelmans J, et al., “Prospective Studyon the Incidence of Chronic Ear Complaints Related to GastroesophagealReflux and on the Outcome of Antireflux Therapy”, Ann Otol RhinolLarvngol, (2002);111:933-938.

[0022] GERD is considered to be a chronic condition for which long-termmedical therapy and/or surgical therapy is often deemed necessary, insignificant part because esophageal adenocarcinoma is sometimes aconsequence of GERD. DeVault K R, et al., “Updated Guidelines for theDiagnosis and Treatment of Gastroesophageal Reflux Disease”, Am JGastroenterol, (1999);94:1434-1442. Lagergren J, et al., “SymptomaticGastroesophageal Reflux as a Risk Factor for Esophageal Adenocarcinoma”,New Engl J Med, (1999);340:825-831.

[0023] The underlying pathophysiological mechanisms in GERD areconsidered to be transient lower esophageal relaxations (TLESRs) in thepresence of either an inadequate pressure gradient between the stomachand the esophagus across the lower esophageal sphincter and/or lowamplitude esophageal activity at times when gastric contents do refluxinto the esophagus. In addition, gastric distention is thought to beassociated with an increase in TLESRs. Mittal R K, et al., “Mechanism ofDisease: The Esophagogastric Junction”, New Engl J Med,(1997);336:924-932. Scheffer R C, et al., “Elicitation of TransientLower Oesophageal Sphincter Relaxations in Response to GastricDistension”, Neurogastroenterol Motil, (2002);14:647-655.

[0024] GERD is generally considered to be the result of a motilitydisorder which permits the abnormal and prolonged exposure of theesophageal lumen to acidic gastric contents. Hunt, “The RelationshipBetween The Control Of pH And Healing And Symptom Relief InGastro-Oesophageal Reflux Disease”, Ailment Pharmacol Ther., 9(Suppl. 1) pp. 3-7 (1995). Many factors are believed to contribute tothe onset of GERD. These include transient lower esophageal sphincterrelaxations (as previously described), decreased LES resting tone,delayed stomach emptying and an ineffective esophageal clearance.

[0025] Certain drugs have had some effectiveness at controlling GERD butfail to treat underlying causes of the disease. Examples of such drugsare H₂-receptor antagonists (which control gastric acid secretion in thebasal state) and proton pump inhibitors (which control meal-stimulatedacid secretion). Hunt, id. Both classes of drugs can raise intragastricpH to or about 4 for varying durations. Hunt, supra.

[0026] Surgery treatments are also employed for the treatment of GERDand include techniques for bulking the lower esophageal sphincter suchas fundoplication and techniques described in U.S. Pat. No. 6,098,629Johnson et al, Aug. 8, 2000. Other surgical techniques include placementof pacemakers for stimulating muscle contractions in the esophagealsphincter, the stomach muscles or in the pyloric valve. U.S. Pat. No.6,104,955 to Bourgeois, U.S. Pat. No. 5,861,014 to Familoni.

[0027] A summary of GERD treatments can be found in DeVault, et al.,“Updated Guidelines for the Diagnosis and Treatment of GastroesophagealReflux Disease”, Amer. J. of Gastroenterology, Vol. 94, No. 6, pp.1434-1442 (1999).

[0028] Notwithstanding multiple attempts at various types of treatment,GERD continues to be a serious disease proving to be difficult to treatby any of the foregoing prior art techniques. In view of the foregoingand notwithstanding various efforts exemplified in the prior art, thereremains a need for an effective treatment for GERD. It is an object ofthe present invention to provide a novel treatment and novel apparatusfor the treatment of GERD.

[0029] D. Electrical Stimulation to Treat GI Disorders

[0030] Treatment of gastrointestinal diseases through nerve stimulationhave been suggested. For example, U.S. Pat. No. 6,238,423 to Bardy datedMay 29, 2001 describes a constipation treatment involving electricalstimulation of the muscles or related nerves of the gut. U.S. Pat. No.6,571,127 to Ben-Haim et al. dated May 27, 2003 describes increasingmotility by applying an electrical field to the GI tract. U.S. Pat. No.5,540,730 to Terry, Jr. et al., dated Jul. 30, 1996 describes a motilitytreatment involving vagal stimulation to alter GI contractions inresponse to a sense condition indicative of need for treatment. The '730patent also uses a definition of dysmotility more restrictive than inthe present application. In the '730 patent, dysmotility is described ashyper- or hypo-contractility. In the present application, dysmotility isa broader concept to refer to all abnormalities of gastric emptying orbowel transfer regardless of cause. U.S. Pat. No. 6,610,713 to Traceydated Aug. 26, 2003 describes inhibiting release of a proinflammatorycytokine by treating a cell with a cholinergic agonist by stimulatingefferent vagus nerve activity to inhibit the inflammatory cytokinecascade.

[0031] A substantial body of literature is developed on nervestimulation. For example, in Dapoigny et al., “Vagal influence oncolonic motor activity in conscious nonhuman primates”, Am. J. Physiol.,262: G231-G236 (1992), vagal influence on colonic motor activity wasinvestigated in conscious monkeys. To block antidromic interference, thevagus was blocked via vagal cooling and a vagal stimulation electrodewas implanted distal to the vagal block. It was noted that vagalefferent stimulation increased contractile frequency and that the vagushas either a direct or indirect influence on fasting and fed colonicmotor activity throughout the colon, and that a non-adrenergic,noncholinergic inhibitory pathway is under vagal control.

[0032] Colonic and gastric stimulation are also described in a number ofarticles associated with M. P. Mintchev. These include: Mintchev, etal., “Electrogastrographic impact of multi-site functional gastricelectrical stimulation”, J. of Medical Eng. & Tech., Vol. 23, No. 1 pp.5-9 (1999); Rashev, et al., “Three-dimensional static parametricmodeling of phasic colonic contractions for the purpose ofmicroprocessor-controlled functional stimulation”, J. of Medical Eng. &Tech., Vol. 25, No. 3 pp. 85-96 (2001); Lin et al., “Hardware—softwareco-design of portable functional gastrointestinal stimulator system”, J.of Medical Eng. & Tech., Vol. 27, No. 4 pp. 164-177 (2003); Amaris etal., “Microprocessor controlled movement of solid colonic content usingsequential neural electrical stimulation”, Gut, 50: pp 475-479 (2002)and Rashev et al., “Microprocessor-Controlled Colonic Peristalsis”,Digestive Diseases and Sciences, Vol. 47, No. 5, pp. 1034-1048 (2002).

[0033] The foregoing references describe nerve stimulation to stimulatemuscular contraction in the GI tract. As will be more fully discussed,the present invention utilizes vagal stimulation to improve vagal tone(similar in concept to improving cardiac electrical tone through cardiacpacing) and/or to treat GI disorders by altering the nature of duodenumcontents by stimulation pancreatic and biliary output. The invention isalso applicable to treating other diseases such as neuropsychiatricdisorders.

[0034] Vagal tone has been shown to be associated with dyspepsia.Hjelland, et al., “Vagal tone and meal-induced abdominal symptoms inhealthy subjects”, Digestion, 65: 172-176 (2002). Also, Hausken, et al.,“Low Vagal Tone and Antral Dysmotility in Patients with FunctionalDyspepsia”, Psychosomatic Medicine, 55: 12-22 (1993). Also, decreasedvagal tone has been associated with irritable bowel syndrome.Heitkemper, et al., “Evidence for Automatic Nervous System Imbalance inWomen with Irritable Bowel Syndrome”, Digestive Diseases and Sciences,Vol. 43, No. 9, pp. 2093-2098 (1998).

[0035] Also, as will be discussed, the present invention includes, inseveral embodiments, a blocking of a nerve (such as the vagal nerve) toavoid antidromic influences during stimulation. Cryogenic nerve blockingof the vagus is described in Dapoigny et al., “Vagal influence oncolonic motor activity in conscious nonhuman primates”, Am. J. Physiol.,262: G231-G236 (1992). Electrically induced nerve blocking is describedin Van Den Honert, et al., “Generation of Unidirectionally PropagatedAction Potentials in a Peripheral Nerve by Brief Stimuli”, Science, Vol.206, pp. 1311-1312. An electrical nerve block is described in Solomonow,et al., “Control of Muscle Contractile Force through IndirectHigh-Frequency Stimulation”, Am. J. of Physical Medicine, Vol. 62, No.2, pp. 71-82 (1983) and Petrofsky, et al., “Impact of Recruitment Orderon Electrode Design for Neural Prosthetics of Skeletal Muscle”, Am. J.of Physical Medicine, Vol. 60, No. 5, pp. 243-253 (1981). A neuralprosthesis with an electrical nerve block is also described in U.S.Patent Application Publication No. U.S. 2002/0055779 A1 to Andrewspublished May 9, 2002. A cryogenic vagal block and resulting effect ongastric emptying are described in Paterson C A, et al., “Determinants ofOccurrence and Volume of Transpyloric Flow During Gastric Emptying ofLiquids in Dogs: Importance of Vagal Input”, Dig Dis Sci,(2000);45:1509-1516.

III. SUMMARY OF THE INVENTION

[0036] A method and apparatus are disclosed for treating at least one ofa plurality of disorders of a patient associated with vagal activityinnervating at least one of a plurality of organs of the patient at aninnervation site. The method includes positioning a neurostimulatorcarrier within a body lumen of the patient. An electrode disposed on thecarrier is positioned near a mucosal layer of the lumen. An electricalsignal is applied to the electrode to modulate vagal activity by anamount selected to treat the disorder. The signal may be a blocking or astimulation signal.

IV. BRIEF DESCRIPTION OF THE DRAWINGS

[0037]FIG. 1 is a schematic representation of a gastric-emptyingfeedback loop with a patient-controlled stimulator for stimulating anorgan of the loop;

[0038]FIG. 2 is a view similar to FIG. 1 with an automatic controllerreplacing the patient-controller of FIG. 1 and with feedback circuits tothe automatic controller schematically represented;

[0039]FIG. 3 is a schematic illustration of an alimentary tract (GItract plus non-GI organs such as the pancreas and liver) and itsrelation to vagal and enteric innervation;

[0040]FIG. 4 is the view of FIG. 3 showing the application of a pacingelectrode according to an embodiment of the present invention;

[0041]FIG. 5 is a schematic representation of pacing system;

[0042]FIG. 6 is the view of FIG. 4 showing the application of a nerveconduction block electrode proximal to the pacing electrode;

[0043]FIG. 7 is the view of FIG. 6 showing the application of a nerveconduction block electrode distal to the pacing electrode;

[0044]FIG. 8 is the view of FIG. 3 showing the application of a nerveconduction block electrode according to an embodiment of the presentinvention;

[0045]FIG. 9 is a schematic representation of a patients' stomach shownpartially in section and illustrating a representative placement ofanterior and posterior vagus nerves with respect to the anatomy of thestomach and diaphragm;

[0046]FIG. 10 is the view of FIG. 9 showing a further embodiment of thepresent invention in utilizing electrode bands;

[0047]FIG. 11 is a perspective view of a band for use in the embodimentof FIG. 10;

[0048]FIG. 12 is a side sectional view of a patients' stomach inillustrating a yet alternative embodiment of the present invention;

[0049]FIG. 13 is a side elevation view of a balloon portion of anapparatus for use in the embodiment of FIG. 12;

[0050]FIG. 14 is a side elevation view of an alternative embodiment of aballoon portion of an apparatus for use in the embodiment of FIG. 12;

[0051]FIG. 15 is a side sectional view of a patients' stomach inillustrating a yet alternative embodiment of the invention of FIG. 12;

[0052]FIG. 16 is a side sectional view of a patients' stomach inillustrating a still further alternative embodiment of the invention ofFIG. 12;

[0053]FIG. 17 is a schematic view of a balloon with magnetic coils;

[0054]FIG. 18 is a side sectional view of the esophagus and stomachjunction and illustrating a yet further embodiment of the presentinvention; and

[0055]FIG. 19 is a view similar to that of FIG. 15 and illustrating analternative embodiment of the invention shown in FIG. 15.

V. DESCRIPTION OF THE PREFERRED EMBODIMENT

[0056] With reference now to the various drawing figures in whichidentical elements are numbered identically throughout, a description ofthe preferred embodiment of the present invention will now be described.

[0057] A. Invention of Parent Application

[0058]FIGS. 1 and 2 and the description which follow are from theaforementioned U.S. patent application Ser. No. 10/358,093 filed Feb. 3,2003 filed Feb. 3, 2003 and entitled “Method and Apparatus for Treatmentof Gastroesophageal Disease (GERD)”.

[0059] With initial reference to FIG. 1, a gastric emptying feedbackloop is shown schematically for ease of illustration. The feedback loopillustrates a patient's stomach S which is provided with food from theesophagus E. A lower esophageal sphincter LES is shown positionedbetween the esophagus E and the stomach S. The lower esophagealsphincter normally provides control of reflux of stomach contents intothe esophagus E.

[0060] On a proximal or lower end of the stomach S the stomachdischarges into the superior duodenum D which is an upper portion of theintestines. The superior duodenum D and the stomach S are separated by apyloric valve PV which opens to permit gastric emptying from the stomachinto the duodenum D.

[0061] Also schematically illustrated in FIG. 1 are nerve paths Nproviding signal flow paths from both the superior duodenum D and thestomach S to the brain B. An efferent Vagal nerve VN connects the brainB to the pancreas P of the patient. A conduit (pancreatic duct PD)extends from the pancreas P and discharges into the superior duodenum D.

[0062] The presence of food contents within the duodenum D (suchcontents being referred to as “chyme”) may prevent passage of gastriccontent of the stomach S past the pyloric valve PV into the duodenum D.As long as such gastric contents cannot be passed into the duodenum D,such contents can be forced retrograde past the lower esophagealsphincter LES and into the esophagus E creating the symptoms anddiscomfort of GERD. The contents discharging from the stomach S into theduodenum D are acidic (and high osmolality) and reside in the duodenum Duntil pH is elevated (close to a neutral pH of 6-7) and osmolality isnormalized.

[0063] The elevation of pH and reduction of osmolality of chyme in theduodenum D results from exocrine secretion being administered from thepancreas P and from bile from the liver into the duodenum D. This raisesthe pH and lowers the osmolality of the duodenum D content permittingdischarge from the duodenum D and thereby permitting gastric emptyingacross the pyloric valve PV.

[0064] According to the present invention gastroesophageal refluxdisease (GERD) results from a derangement of the feedback loops involvedin upper GI digestion and motility control. This problem encompassesreceptors and reflexes that regulate the propulsive contractions of thestomach, upper duodenum and biliary tree and the secretions of theexocrine pancreas. The interaction of these receptors and reflexescontrol gastric emptying (by coordinating gastric propulsivecontractions and sphincter [primarily pyloric] tone) and regulate the pHand osmolality of the chyme in the duodenum. This chemo-regulation ismediated through control of bile delivery and stimulation of secretionby the exocrine pancreas of fluid delivered to the superior duodenum.Chey et al., “Neural Hormonal Regulation of Exocrine PancreaticSecretion”, Pancreatology, pp. 320-335 (2001).

[0065] Normally, ingestate delivered to the stomach is mixed by lowintensity gastric mixing contractions with the enzymatic, ionic,including hydrogen ion (H⁺), and water secretions of the glands of thestomach. When the material is adequately reduced in size and is a smoothconsistency, the fluid, now called chyme, is delivered to the ampulla ofthe small intestine by the much stronger propulsive, or emptying,contractions of the stomach coupled with transitory relaxation of thepyloric sphincter. This material is at a very low pH (about 2) and highosmolality, which activates receptors, including those for H⁺ andosmotic pressure, which are abundant in the wall of the ampulla. Thisreceptor activation initiates the series of reflexes that causepancreatic exocrine secretion to be delivered into the superior duodenumand ampulla. This fluid contains digestive enzymes, water and bufferingcompounds to raise the pH, and reduce the osmolality, of the chyme.

[0066] Once a neutral pH and physiological osmolality are achieved, thenpropulsive contractions in the superior duodenum move the chyme out ofthe superior portion into the length of the duodenum; At which point thestretch and baro-receptors in the ampulla allow the pyloric sphincter torelax and another bolus of gastric contents is delivered into theampulla by the peristaltic gastric emptying contractions. This material,at a very low pH (less than 2), activates hydrogen ion (H⁺) on receptorsof the ampulla (upper most portion of the duodenum) causing thepancreatic fluids to be delivered to the material in the ampullarestarting the cycle as described above. Chapter 3, “The Stomach”,Gastrointestinal System, 2^(nd) Ed., M. S. Long editor, Mosby Publisher,London (2002).

[0067] If the control system is down regulated by, for example, byincreased pH of gastric contents entering the ampulla, feedback maythereby be reduced from the H⁺ receptors in the duodenum that stimulatepancreatic exocrine secretion and bile delivery to the duodenum, thenmovement of chyme from the superior duodenum is delayed, causing delayof gastric emptying. Mabayo, et al., “Inhibition of Food Passage byOsmeprazole in the Chicken”, European J. of Pharmacology, pp. 161-165(1995).

[0068] In GERD, this reflex is inhibited in such a way that the stomachempties more slowly so that the gastric emptying contractions forcegastric contents to flow retrograde into the esophagus. This is a resultof the situation in which the gastric emptying contractions are vigorousbut must operate against a contracted pyloric sphincter. These vigorousperistaltic contractions eventually begin to force gastric contents toflow retrograde into the esophagus because of the inherent imbalancebetween a very strong pyloric sphincter and a much weakergastroesophageal sphincter. The delay in gastric emptying is directlyrelated to a slow down in the transport of chyme out of the ampulla andsuperior duodenum. The drugs used to treat this disease raise pH furtherdampening the hydrogen-receptor-pancreatic secretion loop, furtherdelaying gastric emptying. Benini, “Gastric Emptying and DyspepticSymptoms in Patients with Gastroesophageal Reflux”, Amer. J. ofGastroenterology, pp. 1351-1354 (1996).

[0069] The present invention is directed towards reestablishing the linkbetween gastric emptying and pancreatic secretion delivery, therebyaddressing the main pathology of this disease by shortening chymeresidence time in the superior duodenum so that intestinal contents moveinto the distal digestive tract in a more normal manner. According to afirst embodiment, this is done by stimulating the H+ ion receptors or bystimulation of the pancreas directly or via its para-sympatheticinnervation (pre-ganglionic Vagal nerves). Stimulation of pancreaticexocrine secretion has been shown by direct stimulation of the thoracicvagus nerves in dogs. Kaminski et al., “The Effect of Electrical VagalStimulation on Canine Pancreatic Exocrine Function”, Surgery, pp.545-552 (1975). This results in a more rapid (normal) neutralization ofchyme in the ampulla, allowing it move down the duodenum more quickly sothat gastric emptying is returned to a more normal pace.

[0070] Acidity (pH) can be assessed by measuring bicarbonate. It will beunderstood that references to -H includes such indirect measurements.Also, effects of the therapy described herein can be assessed and/orcontrolled by measuring an indication of pancreatic exocrine secretionor bile (e.g., HCO₃ ⁻).

[0071] An alternative embodiment uses gastrocopic delivery of aparalyzing agent (e.g. botulism toxin) to the pyloric valve along withuse of H2 antagonists or PPI's to manage the acidity of the chymereaching the duodenum.

[0072] As an additional alternative to pancreatic stimulation, the gallbladder can be stimulated to encourage bile movement into the duodenum.Shown schematically in the figures, the gall bladder, GB resides belowthe liver L. The gall bladder is connected to the small intestine(specifically the duodenum D) via a bile duct BD. The bile duct BD candischarge directly into the duodenum D or via the pancreatic duct PD asshown. The bile can normalize the chyme to accelerate duodenal emptying.Bile consists of bile acids (detergents that emulsify lipids),cholesterol, phospholipids, electrolytes such as (Na⁺, K⁺, Ca⁺², C⁻,HCO₃ ⁻) and H₂O. Chapter 4, “The Liver and Biliary Tract”,Gastrointestinal System, 2^(nd) Ed., M. S. Long editor, Mosby Publisher,London (2002). The gall bladder GB or bile duct can be stimulatedindirectly via stimulation of the vagal nerve VN or directly stimulatedby an electrode 11 (shown in phantom lines).

[0073] As illustrated in the figures, an electrical stimulator 10, 20which may be implanted is provided which alternatively may be directlyconnected to the Vagal nerve VN or the pancreas P to stimulate thepancreas directly or indirectly to excrete exocrine into the duodenum D(or more distally into the small intestine—e.g., into the jejunum) andincrease the pH of chyme in the duodenum D as described. Alternatively,the same can be done to promote bile release. The frequency may bevaried to maximize the response and selectively stimulate exocrineinstead of endocrine secretions. Rosch et al., “Frequency-DependentSecretion of Pancreatic Amylase, Lipase, Trypsin, and ChymotrypsinDuring Vagal Stimulation in Rats”, Pancreas, pp. 499-506 (1990). See,also, Berthoud et al., “Characteristics of Gastric and PancreaticReponses to Vagal Stimulation with Varied Frequencies: Evidence forDifferent Fiber Calibers?”, J. Auto. Nervous Sys., pp. 77-84 (1987)(showed frequency-response relationship with insulin, i.e.,significantly less insulin was released at lower frequencies—2 Hz v. 8Hz—also, frequency-response curves evidenced distinctly differentprofiles for gastric, pancreatic and cardiovascular responses.) Slightinsulin release can maximize pancreatic exocrine secretion. Chey et al.,“Neural Hormonal Regulation of Exocrine Pancreatic Secretion”,Pancreatology, pp. 320-335 (2001).

[0074] With a patient control stimulation as shown in FIG. 1, thepatient may activate the stimulator 10 by remote transmitter tostimulate an electrical charge either after eating (e.g., about 60 to 90minutes after eating) or on onset of GERD symptoms. It will beappreciated that there are a wide variety of nerve stimulators and organstimulators available for implantation and are commercially availableand which include connectors for connecting directly to nerves.

[0075]FIG. 2 illustrates an additional embodiment where the patientactivated loop is replaced with an automatic loop having a programmablestimulator 20 which receives as an input signals from sensors in theduodenum to measure pH, osmolality or strain (e.g., from baro-sensors)on the duodenum indicating filling or may measure acidity in theesophagus or strain on the lower esophageal sphincter LES or stomach Sall of which may be provided to the implantable controller 20 which canbe provided with desirable software to process the incoming signals andgenerate a stimulating signal to either the vagal nerve, the pancreas Por the duodenum D (or jejunum) directly in response to such receivedsignals. It will be appreciated that stimulators and controllers arewell within the skill of the art. U.S. Pat. No. 5,540,730 teaches aneurostimulator to stimulate a vagus nerve to treat a motility disorder.U.S. Pat. No. 5,292,344 teaches gastrointestinal sensors, including pHsensors.

[0076] B. Application of Parent Application to Treatments Other thanGERD

[0077] In addition to treatment of GERD, the foregoing invention isapplicable to treatment of a plurality of GI diseases associated withdelayed gastric emptying or altered autonomic activity. These includefunctional gastrointestinal disorders and gastroparesis. Furthermore,applicants have determined that duodenal content impacts a plurality ofmotility disorders throughout the bowels and can diseases associatedwith dysmotility (e.g., irritable bowel syndrome). Accordingly it is anobject of the present invention to use the teachings of theaforementioned parent application to treat GI disorders associated withdelayed gastric emptying and abnormal intestinal transport.

[0078] C. Additional Disclosure of the Present Application

[0079] 1. Enteric Innervation

[0080]FIG. 3 is a schematic illustration of an alimentary tract (GItract plus non-GI organs such as the pancreas and ball bladder,collectively labeled PG) and its relation to vagal and entericinnervation. The lower esophageal sphincter (LES) acts as a gate to passfood into the stomach S and, assuming adequate function of allcomponents, prevent reflux. The pylorus PV controls passage of chymefrom the stomach S into the intestines I (collectively shown in thefigures and including the large intestine or colon and the smallintestine including the duodenum, jejunum and ileum).

[0081] The biochemistry of the contents of the intestines I isinfluenced by the pancreas P and gall bladder PG which discharge intothe duodenum. This discharge is illustrated by dotted arrow A.

[0082] The vagus nerve VN transmits signals to the stomach S, pylorusPV, pancreas and gall bladder PG directly. Originating in the brain,there is a common vagus nerve VN in the region of the diaphragm (notshown). In the region of the diaphragm, the vagus VN separates intoanterior and posterior components with both acting to innervate the GItract. In FIGS. 3, 5-8, the anterior and posterior vagus nerves are notshown separately. Instead, the vagus nerve VN is shown schematically toinclude both anterior and posterior nerves.

[0083] The vagus nerve VN contains both afferent and efferent componentssending signals away from and to, respectively, its innervated organs.

[0084] In addition to influence from the vagus nerve VN, the GI andalimentary tracts are greatly influenced by the enteric nervous systemENS. The enteric nervous system ENS is an interconnected network ofnerves, receptors and actuators throughout the GI tract. There are manymillions of nerve endings of the enteric nervous system ENS in thetissues of the GI organs. For ease of illustration, the enteric nervoussystem ENS is illustrated as a line enveloping the organs innervated bythe enteric nervous system ENS

[0085] The vagus nerve VN innervates, at least in part, the entericnervous system ENS (schematically illustrated by vagal trunk VN3 whichrepresents many vagus-ENS innervation throughout the cut). Also,receptors in the intestines I connect to the enteric nervous system ENS.Arrow B in the figures illustrates the influence of duodenal contents onthe enteric nervous system ENS as a feedback to the secretion finctionof the pancreas, liver and gall bladder. Specifically, receptors in theintestine I respond the biochemistry of the intestine contents (whichare chemically modulated by the pancreaobiliary output of Arrow A). Thisbiochemistry includes pH and osmolality.

[0086] In the figures, vagal trunks VN1, VN2, VN4 and VN6 illustrateschematically the direct vagal innervation of the GI organs of the LES,stomach S, pylorus PV and intestines I. Trunk VN3 illustrates directcommunication between the vagus VN and the ENS. Trunk VN5 illustratesdirect vagal innervation of the pancreas and gall bladder. Entericnerves ENS1-ENS4 represent the multitude of enteric nerves in thestomach S, pylorus PV, pancreas and gall bladder PG and intestines I.

[0087] While communicating with the vagus nerve VN, the enteric nervoussystem ENS can act independently of the vagus and the central nervoussystem. For example, in patients with a severed vagus nerve (vagotomy—anhistorical procedure for treating ulcers), the enteric nervous systemcan operate the gut. Most enteric nerve cells are not directlyinnervated by the vagus. Gershon, “The Second Brain”, Harper CollinsPublishers, Inc, New York, N.Y. p. 19 (1998)

[0088] In FIG. 3, the vagus VN and its trunks (illustrated as VN1-VN6)and the enteric nervous system ENS are shown in phantom lines toillustrate reduced vagal and enteric nerve tone (i.e., sub-optimal nervetransmission levels). Reduced vagal and enteric tone contribute directlyto the ineffectiveness of the GI organs as well as indirectly (throughreduced pancreatic/biliary output). The reduced pancreatic/biliaryoutput is illustrated by the dotted presentation of arrow A. Aspreviously discussed, the vagus can be stimulated to stimulatepancreatic or biliary output. Therefore, the reduced output of arrow Aresults in a reduced feedback illustrated by the dotted presentation ofarrow B.

[0089] 2. Enteric Rhythm Management (ERM)

[0090] The benefits of the present invention are illustrated in FIG. 4where a stimulating or pacing electrode PE is applied to the vagus VN.While only one electrode is shown in FIG. 4, separate electrodes couldbe applied to both the anterior and posterior vagus nerves (or to thecommon vagus or vagal branches). In a preferred embodiment, theelectrode PE is placed a few centimeters below the diaphragm andproximal to stomach and pancreo/biliary innervation. While thisplacement is presently preferred for ease of surgical access, otherplacement locations may be used.

[0091] By pacing the vagus through the pacing electrode, vagal tone isoptimized by either up- or down-regulation. With reference to theparasympathetic and enteric nervous systems, “tone” refers to basalactivity of a nerve or nervous system facilitating appropriatephysiologic response to a patient's internal environment. For example,low vagal tone implies a reduction in vagus nerve activity resulting indecreased response of the alimentary tract to ingested food. As used inthe present application, “pacing” is not limited to mean timed eventscoordinated with specifically timed physiologic events. Instead, pacingmeans any electrical stimulation of a nerve trunk to inducebi-directional propagation of nervous impulses in the stimulated nerve.

[0092] The operating effectiveness of the vagus is enhanced so thatlocal physiological signals generated in the enteric nervous system (orsent to the brain from the organs) are more appropriately responded towithin the alimentary tract. Due to its innervation of the entericnervous system, pacing of the vagus enhances the functional tone of theenteric nervous system. By enhancing the functional tone it will benoted that the stimulation pacing is elevating the degree offunctionality of the vagus and enteric nerves. In this context, “pacing”is not meant to mean timed pulsed coordinated with muscular contractionsor synchronized with other invents. Pacing means elevating the activitylevel of the nerves.

[0093] Tonal enhancement of the vagus and enteric nerves is illustratedby the solid lines for the nerves VN, ENS in FIG. 4. Vagal trunk VN5 isin solid line to illustrate enhanced tone of the many vagal nervecomponents communicating with the enteric nervous system ENS. Directvagal innervation of the LES, stomach S, pylorus PV and intestines Iremains shown as low tone indicated by phantom lines VN1, VN2, VN4, VN6.The tonal pacing described herein is not intended to trigger or drivethe muscular contractility of these organs. The stimulation is notintended to be timed to trigger contractility and is not provided withan energy level sufficient to drive peristaltic contractions. Instead,these functions remain controlled by the central and enteric nervessystems. The enhanced nerve tone provided by the present inventionpermits these functions to occur.

[0094] Pacing to enhance vagal tone is not initiated in response to anysenses event (or in anticipation of an immediate need to GI activity).Instead, the pacing can be done intermittently over the day to providean enhanced level of operating functionality to the vagus. By way ofnon-limiting example, the stimulation pacing can be done during awakehours. For example, every ten minutes, pacing signals can be sent to thepacing electrodes. The pacing signals have a duration of 30 seconds witha current of 4 mA, a frequency of 12 Hz and an impulse duration of 2msec. These parameters are representative only. A wide range of signalparameters may be used to stimulate the vagus nerve. Examples of theseare recited in the afore-referenced literature

[0095] As will be further discussed, the present invention permits ERMto be uniquely designed and modified by an attending physician to meetthe specific needs of individual patients. For example, pacing can belimited to discrete intervals in the morning, afternoon and evening withthe patient free to coordinate meals around these events.

[0096] In addition to enhancing vagal and enteric tone directly, thepacing also enhances the pancreatic and biliary output for the reasonsdiscussed above. Namely, while ERM does not drive muscular events overnerve trunks VN1, VN2, VN4, VN6, the enhanced tone stimulatespancreo-biliary output over trunk VN5 (illustrated by the solid line ofVN5 in FIG. 4). This enhanced output is illustrated as solid arrow A′ inFIG. 4. As a consequence there is a greater feedback to the intestinalreceptors as illustrated by solid arrow B′ in FIG. 4. This enhancedbiochemistry feedback further enhances the tone of the enteric nervoussystem ENS.

[0097] 3. Implantable Pacing Circuit

[0098] A representative pacing circuit 100 is schematically shown inFIG. 5. Similar to cardiac pacing devices, an implantable controller 102contains an induction coil 104 for inductive electrical coupling to acoil 106 of an external controller 108. The implantable controller 102includes anterior and posterior pulse generators 110, 112 electricallyconnected through conductors 114, 116 to anterior and posterior pacingelectrodes 118, 120 for attachment to anterior and posterior trunks,respectively, of the vagus nerve VN. The implantable controller 102 alsoincludes a battery 122 and a CPU 124 which includes program storage andmemory. The timing and parameters of the pulse at the electrodes 118,120 can be adjusted by inductively coupling the external controller 108to the implantable controller 102 and inputting pacing parameters (e.g.,pulse width, frequency and amplitude).

[0099] While a fully implantable controller 102 is desirable, it is notnecessary. For example, the electrodes 118, 120 can be implantedconnected to a receiving antenna placed near the body surface. Thecontrol circuits (i.e., the elements 124, 110, 112 and 108) can behoused in an external pack worn by the patient with a transmittingantenna held in place on the skin over the area of the implantedreceiving antenna. Such a design is forward-compatible in that theimplanted electrodes can be later substituted with the implantablecontroller 102 at a later surgery if desired.

[0100] Although not shown in FIG. 5, the controller 102 can also includecircuits generating nerve conduction block signals (as will bedescribed) which connect to electrodes which may be positioned on anerve proximally, distally (or both) of the electrodes 118, 120.

[0101] 4. Nerve Conduction Block

[0102]FIG. 6 shows an alternative embodiment using a nerve conductionblocking electrode PBE proximal to the pacing electrode for providing aconduction block. A nerve block is, functionally speaking, a reversiblevagotomy. Namely, application of the block at least partially preventsnerve transmission across the site of the block. Removal of the blockrestores normal nerve activity at the site. A block is any localizedimposition of conditions that at least partially diminish transmissionof impulses.

[0103] The vagal block may be desirable in some patients since unblockedpacing may result in afferent vagal and antidromic efferent signalshaving undesired effect on organs innervated by the vagus proximal tothe GI tract (e.g., undesirable cardiac response). Further, the afferentsignals of the pacing electrode PE can result in a central nervoussystem response that tends to offset the benefits of the pacingelectrode on the ENS and pancreo/biliary function. thereby reducing theGI and enteric rhythm management effectiveness of vagal pacing.

[0104] The block may be intermittent and applied only when the vagus ispaced by the pacing electrode PE. The preferred nerve conduction blockis an electronic block created by a signal at the vagus by an electrodePBE controlled by the implantable controller (such as controller 102 oran external controller). The nerve conduction block can be anyreversible block. For example, cryogenics (either chemically orelectronically induced) or drug blocks can be used. An electroniccryogenic block may be a Peltier solid-state device which cools inresponse to a current and may be electrically controlled to regulatecooling. Drug blocks may include a pump-controlled subcutaneous drugdelivery.

[0105] With such an electrode conduction block, the block parameters(signal type and timing) can be altered by a controller and can becoordinated with the pacing signals to block only during pacing. Arepresentative blocking signal is a 500 Hz signal with other parameters(e.g., timing and current) matched to be the same as the pacing signal).While an alternating current blocking signal is described, a directcurrent (e.g., −70 mV DC) could be used. The foregoing specific examplesof blocking signals are representative only. Other examples and rangesof blocking signals are described in the aforementioned literature (allincorporated herein by reference). As will be more fully described, thepresent invention gives a physician great latitude in selected pacingand blocking parameters for individual patients.

[0106] Similar to FIG. 4, the vagus VN and enteric nervous system ENS inFIG. 6 distal to the block PBE are shown in solid lines to illustrateenhanced tone (except for the direct innervation VN1, VN2, VN4, VN6 tothe GI tract organs). Similarly, arrows A′, B′ are shown in solid linesto illustrate the enhanced pancreo-biliary output and resultant enhancedfeedback stimulation to the enteric nervous system ENS. The proximalvagus nerve segment VNP proximal to the block PBE is shown in phantomlines to illustrate it is not stimulated by the pacing electrode PEwhile the blocking electrode PBE is activated.

[0107] 5. Proximal and Distal Blocking

[0108]FIG. 7 illustrates the addition over FIG. 6 of a nerve conductiveblock DBE distal to the pacing electrode PE. The proximal block PBEprevents adverse events resulting from afferent signals and heightensthe GI effectiveness by blocking antidromic interference as discussedwith reference to FIG. 6.

[0109] In FIG. 7, the distal block DBE is provided in the event there isa desire to isolate the pacing effect of electrode PE. For example, aphysician may which to enhance the vagus and enteric activity in theregion proximal to the duodenum but may wish to avoid stimulatingpancreo-biliary output. For example, a patient may have a GI problemwithout apparent colon dysfunction (e.g., gastroparesis functionaldyspepsia without bowel symptoms). Placing the distal block DBE on abranch of the vagus between the pacing electrode PE and the pancreas andgall bladder PG prevents increased pancreo-biliary output and resultantfeedback (illustrated by dotted arrows A and B in FIG. 7 and dotteddistal vagal nerve segment VND and vagal trunk VN5).

[0110] 6. Blocking As An Independent Therapy

[0111]FIG. 8 illustrates an alternative embodiment of the invention.

[0112] In certain patients, the vagus nerve may be hyperactivecontributing to diarrhea-dominant IBS. Use of a blocking electrode alonein the vagus permits down-regulating the vagus nerve VN, the entericnervous system ENS and pancreo-biliary output. The block down-regulatesefferent signal transmission. In FIG. 8, the hyperactive vagus isillustrated by the solid line of the proximal vagus nerve segment VNP.The remainder of the vagus and enteric nervous system are shown inreduced thickness to illustrate down-regulation of tone. Thepancreo-biliary output (and resulting feedback) is also reduced. In FIG.8, the blocking electrode BE is shown high on the vagus relative to theGI tract innervation (e.g., just below the diaphragm), the sole blockingelectrode could be placed lower (e.g., just proximal to pancreo/biliaryinnervation VN5).

[0113] The use of blocking as an independent therapy also permitstreatment for pancreatitis by down regulating vagal activity andpancreatic output including pancreatic exocrine secretion. Also, theblocking may be used as a separate treatment for reducing discomfort andpain associated with gastrointestinal disorders or other vagallymediated pain (i.e., somatic pain sensations transmitted along any nervefibers with pain sensation modulated by vagal afferent fibers). A nervestimulation to treat pain is described in U.S. patent applicationpublication No. US2003/0144709 to Zabara et al., published Jul. 31,2003.

[0114] It will be appreciated that patient discomfort and pain is aprimary complaint associated with many gastrointestinal disorders. Asused in the present application (and appended claims), it will beappreciated that a treatment of a gastrointestinal disorder may includea treatment of a patient's perception of pain without any additionalfunctional therapy associated with a gastrointestinal disorder. Vagalblocking as described herein can treat gastrointestinal pain ordiscomfort (including that associated with Crohn's disease) and chronicsomatic pain as well as the inflammatory basis of Crohn's disease. Thevagal blocking as described herein can also treat nausea secondary, forexample, to chronic cancer chemotherapy.

[0115] 7. Application to Obesity

[0116] The foregoing discussion has been described in a preferredembodiment of treating FGIDs, gastroparesis and GERD. Obesity is alsotreatable with the present invention.

[0117] Recent literature describes potential obesity treatments relativeto gut hormone fragment peptide YY₃₋₃₆. See, e.g., Batterham, et al.,“Inhibition of Food Intake in Obese Subjects by Peptide YY3-36”, NewEngland J. Med., pp. 941-948 (Sep. 4, 2003) and Komer et al., “To Eat orNot to Eat—How the Gut Talks to the Brain”, New England J. Med., pp.926-928 (Sep. 4, 2003). The peptide YY₃₋₃₆ (PPY) has the effect ofinhibiting gut motility through the phenomena of the ileal brake. Vagalafferents create a sensation of satiety.

[0118] The present invention can electrically simulate the effects ofPPY by using the vagal block to down-regulate afferent vagal activity tocreate a desired sensation of satiety. Since the down-regulation doesnot require continuous blocking signals, the beneficial efferent signalsare permitted.

[0119] 8. Application to Other Therapies

[0120] There are numerous suggestions for vagal pacing or stimulation totreat a wide variety of diseases. For example, U.S. Pat. No. 5,188,104dated Feb. 23, 1993 describes vagal stimulation to treat eatingdisorders. U.S. Pat. No. 5,231,988 dated Aug. 3, 1993 describes vagalstimulation to treat endocrine disorders. U.S. Pat. No. 5,215,086 datedJun. 1, 1993 describes vagal stimulation to treat migraines. U.S. Pat.No. 5,269,303 dated Dec. 14, 1993 describes vagal stimulation to treatdementia. U.S. Pat. No. 5,330,515 dated Jul. 19, 1994 describes vagalstimulation to treat pain. U.S. Pat. No. 5,299,569 dated Apr. 5, 1994describes vagal stimulation to treat neuropsychiatric disorders. U.S.Pat. No. 5,335,657 dated Aug. 9, 1994 describes vagal stimulation totreat sleep disorders. U.S. Pat. No. 5,707,400 dated Jan. 13, 1998describes vagal stimulation to treat refractory hypertension. U.S. Pat.No. 6,473,644 dated Oct. 29, 2002 describes vagal stimulation to treatheart failure. U.S. Pat. No. 5,571,150 dated Nov. 5, 1996 describesvagal stimulation to treat patients in comas. As previously described,U.S. Pat. No. 5,540,730 dated Jul. 30, 1996 describes vagal stimulationto treat motility disorders and U.S. Pat. No. 6,610,713 dated Aug. 26,2003 describes vagal stimulation to inhibit inflammatory cytokineproduction. All of the foregoing U.S. patents listed in this paragraphare incorporated herein by reference.

[0121] All of the foregoing suffer from undesired effects of vagalpacing on cardiovascular, gastrointestinal or other organs. Nerveconduction blocking permits longer pulse durations which would otherwisehave adverse effects on other organs such as those of the cardiovascularor gastrointestinal systems. In accordance with the present invention,all of the foregoing disclosures can be modified by applying a blockingelectrode and blocking signal as disclosed herein to prevent adverseside effects. By way of specific example, pacing a vagus nerve in thethoracic cavity or neck combined with a blocking electrode on the vagusnerve distal to the pacing electrode can be used to treatneuropsychiatric disorders (such as depression and schizophrenia) andParkinson's and epilepsy and dementia. In such treatments, the blockingelectrode is placed distal to the stimulating electrode 25 shown inFIGS. 4 and 2, respectively, of each of U.S. Pat. Nos. 5,269,303 and5,299,569. The present invention thereby enables the teachings of theafore-referenced patents listed in foregoing two paragraphs.

[0122] As described, the parameters of the stimulating and blockingelectrodes can be inputted via a controller and, thereby, modified by aphysician. Also, FIG. 2 illustrates a feedback for controlling astimulating electrode. Feedbacks for stimulating electrodes are alsodescribed in the patents incorporated by reference. The blockingelectrode can also be controlled by an implanted controller and feedbacksystem. For example, physiologic parameters (e.g., heart rate, bloodpressure, etc.) can be monitored. The blocking signal can be regulatedby the controller to maintain measured parameters in a desired range.For example, blocking can be increased to maintain heart rate within adesired rate range during stimulation pacing.

[0123] 9. Opportunity for Physician to Alter Treatment for SpecificPatient

[0124] Gastrointestinal disorders are complex. For many, the precisemechanism is of the disorder is unknown. Diagnosis and treatment areoften iterative processes. The present invention is particularlydesirable for treating such disorders.

[0125] Use of proximal and distal blocking electrodes in combinationwith one or more pacing electrode permits a physician to alter anoperating permutation of the electrodes. This permits regional and localup- or down-regulation of the nervous system and organs. Further, pacingparameters (duty cycle, current, frequency, pulse length) can all beadjusted. Therefore, the treating physician has numerous options toalter a treatment to meet the needs of a specific patient.

[0126] In addition, a physician can combine the present invention withother therapies (such as drug therapies like prokinetic agents).

[0127] D. Alternative Embodiments

[0128] 1. Background

[0129] With reference to FIG. 9, a stomach S is shown schematically forthe purpose of facilitating an understanding of alternative embodimentsof the invention as illustrated in FIGS. 10-15. In FIG. 9, the stomach Sis shown with a collapsed fundus F which is deflated due to fasting. Inpractice, the fundus F can be reduced in size and volume (as shown inFIG. 9) or expanded (as shown in FIG. 12).

[0130] The esophagus E passes through the diaphragm D at an opening orhiatus H. In the region where the esophagus E passes through thediaphragm D, trunks of the vagal nerve (illustrated as the anteriorvagus nerve AVN and posterior vagus nerve PVN) are disposed on oppositesides of the esophagus E. It will be appreciated that the preciselocation of the anterior and posterior vagus nerves AVN, PVN relative toone another and to the esophagus E are subject to a wide degree ofvariation within a patient population. However, for most patients, theanterior and posterior vagus nerves AVN, PVN are in close proximity tothe esophagus E at the hiatus H where the esophagus E passes through thediaphragm D.

[0131] The anterior and posterior vagus nerves AVN, PVN divide into aplurality of trunks that innervate the stomach directly and via theenteric nervous system and may include portions of the nerves which mayproceed to other organs such as the pancreas, gallbladder andintestines. Commonly, the anterior and posterior vagus nerves AVN, PVNare still in close proximity to the esophagus E and stomach (and not yetextensively branched out) at the region of the junction of the esophagusE and stomach S.

[0132] In the region of the hiatus H, there is a transition fromesophageal tissue to gastric tissue. This region is referred to as theZ-line (labeled “Z” in the Figures). Above the Z-line, the tissue of theesophagus is thin and fragile. Below the Z-line, the tissue of theesophagus E and stomach S are substantially thickened and more vascular.Within a patient population, the Z-line is in the general region of thelower esophageal sphincter. This location may be slightly above,slightly below or at the location of the hiatus H.

[0133] 2. Implanted Band Electrode

[0134] a. Description of Device

[0135] With reference to FIG. 10, a band 200 is shown placed around theesophagus E below the diaphragm D and overlying the anterior andposterior vagus nerves AVN, PVN at the cardiac notch CN. Alternatively,it can be placed completely around the upper portion of the stomach nearits junction of the esophagus. Placement of a band 200 around theesophagus E directly beneath the diaphragm D ensures that the band maybe placed around the anterior and posterior vagus nerves AVN, PVNwithout the need for extensive dissection of the nerves AVN, PVN.

[0136] The band 200 may be formed of polyester or the like or any othersuitable material which may be sutured in place or otherwise fastened inplace surrounding the esophagus E or gastric cardia. Preferably, theband 200 is placed at the junction of the esophagus E and stomach S suchthat the band may overly both the esophagus E and stomach S at thecardiac notch CN.

[0137] The band 200 may have a plurality of electrodes which, in theembodiment of FIG. 10 include an upper electrode array 202 and a lowerelectrode array 203. In the embodiment of FIG. 11 (in which a band 200is shown lying flat), the electrode arrays 202, 203 are shown withelectrodes placed at an angle relative to the cylindrical axis X-X ofthe band 200.

[0138] Placement of the band 200 as described ensures that at least asubset of the electrodes 202, 203 will be in overlying relation to theanterior and posterior vagus nerves AVN, PVN. As a result, energizingthe electrodes 202, 203 will result in stimulation of the anterior andposterior vagus nerves AVN, PVN and/or their branches.

[0139] In therapeutic applications, the upper array 202 of electrodesmay be connected to a blocking electrical signal source (with a blockingfrequency and other parameters as previously described) and the lowerarray 203 of electrodes may be connected to a stimulation electricalsignal source as previously described. Of course, only a single array ofelectrodes could be used with all electrodes connected to either ablocking or a stimulating signal.

[0140] The electrical connection of the electrodes 202, 203 to acontroller is not shown but may be as previously described by having aleads connecting the electrodes directly to an implantable controller.Alternatively, and as previously described, electrodes may be connectedto an implanted antenna for receiving a signal to energize theelectrodes.

[0141] The use of an array of electrodes permits the collar 200 to beplaced without the need for great accuracy at the time of placement. Inthe event it is desirable that electrodes not directly overlying a vagusnerve be deactivated, the electrodes could, through operation of acontroller, be individually energized to detect a physiologicalresponse. The absence of a physiological response (other than possiblemuscular action of the stomach and esophagus) would indicate the absenceof an overlying relation to a vagus nerve. The presence of aphysiological response would indicate overlying relation of the testedelectrode to a vagus nerve.

[0142] By identifying which electrodes create a physiologic response,the remaining electrodes (i.e., those not having a physiologicalresponse) could be permanently deactivated. An example of aphysiological response would be a cardiovascular response which may beattributed to a signal of about 2-80 hertz and up to 50 milliamps and asmore fully described in U.S. Pat. No. 6,532,388 to Hill et al dated Mar.11, 2003. As a result, a selected one of the AVN or PVN could beenergized.

[0143] It will be appreciated the foregoing description of identifyingelectrodes to be deactivated is a non-limiting embodiment. For example,all electrodes could be energized. The therapies as previously describedcould be employed by using blocking electrodes or stimulation electrodesor both in order to block or energize (or both) the vagus nerve.

[0144]FIG. 10 also illustrates an alternative embodiment in the form ofa band 200′ surrounding the body of the stomach S and having arrays202′, 203′. Since the band 200′ is more distal to the esophagus E,different and more distal trunks of the vagus nerves would be energized.Also, such a placement would permit the option of covering the anteriorvagus nerve while not covering the posterior vagus nerve (or visaversa).

[0145] With the embodiment shown in FIG. 10, the benefits of vagalstimulation with resulting enteric rhythm management and theaforementioned benefits of blocking can be achieved without the need forextensive dissection of the vagus nerve. Further, the benefits can beachieved without the need for directly clamping electrodes on a vagusnerve, thereby reducing the possibility of injury to a vagus nerve.

[0146] In addition to the benefits of nerve stimulation, the band 200can also be used to restrict and potentially lengthen the esophagusthereby reducing possibilities for reflux as more fully described incommonly assigned and co-pending U.S. patent application Ser. No.10/600,080 filed Jun. 20, 2003 and entitled “Gastro-Esophageal RefluxDisease” (GERD) Treatment Method and Apparatus”.

[0147] b. Application to Obesity and Satiety

[0148] The embodiment of FIG. 10 is particularly suitable for thetreatment of obesity. Obesity is of epidemic proportions and isassociated with large decreases in life expectancy and early mortality.Peeters, et al., “Obesity in Adulthood and Its Consequences for LifeExpectancy: A Life Table Analysis”, Annals of Internal Medicine, Vol.138, No. 1, pp. 24-32 (2003).

[0149] In the embodiment of FIG. 10, the upper band 200 is placed aroundthe stomach near the cardiac notch CN. Electrode array 202 may bede-activated (or not present on the band 200). Lower array 203 can beenergized with a blocking signal.

[0150] The prior art suggests stimulating the vagas with a stimulatingsignal for treating obesity or eating disorders. See, e.g., U.S. Pat.No. 5,188,104 to Wernicke et al., dated Feb. 23, 1993; U.S. Pat. No.5,263,480 to Wernicke et al., dated Nov. 23, 1993; U.S. Pat. No.6,587,719 to Barrett et al., dated Jul. 1, 2003 and U.S. Pat. No.6,609,025 to Barrett et al., dated Aug. 19, 2003. These patents alldescribe stimulating, non-blocking signals (e.g., stimulating to a levelslightly below a so-called “retching threshold” as described in the '025patent). As such, all fail to note the problem associated with obesityand eating discords that is not addressed by stimulating the vagus but,rather, by blocking stimulation on the vagus.

[0151] The blocking at cardiac notch CN reduces fundal accommodation andcreates satiety sensations. Such a physiologic response is suggested byvagotomy data in which truncal vagotomy patients have experienced weightloss and increased satiety. See, e.g., Kral, “Vagotomy as a Treatmentfor Morbid Obesity”, Surg. Clinics of N. Amer., Vol. 59, No. 6, pp.1131-1138 (1979), Gortz, et al., “Truncal Vagotomy Reduces Food andLiquid Intake in Man”, Physiology & Behavior, Vol. 48, pp. 779-781(1990), Smith, et al., “Truncal Vagotomy in Hypothalamic Obesity”, TheLancet, pp. 1330-1331 (1983) and Kral, “Vagotomy for Treatment of SevereObesity”, The Lancet, pp. 307-308 (1978).

[0152] The optional lower band 200′ is placed lower on the stomach(e.g., close to the pylorus). The lower electrode array 203′ of thelower band 200′ is energized with a stimulation signal to modulateintestinal motility in the event motility is otherwise impaired by theupper band blocking.

[0153] The upper array 202′ of the lower band 200′ is energized with ablocking signal so that the stimulation signal at electrodes 203′ doesnot interfere with the blocking effect of electrodes 203 of upper band200. In this obesity treatment, the electrodes of the bands 200, 200′can be placed on constricting bands (such as the well-known Lap-Band®system of Inamed Inc., Santa Barbara, Calif., USA, and used in obesitytreatment). More preferably, the bands 200, 200′ are not constrictingthereby minimizing erosion risks otherwise associated with highlyconstricting bands. However, the neural blocking technology of thepresent invention can be incorporated into such constricting bands orused in conjunction other obesity surgeries or therapies. Specifically,the scientific literature indicates a vagotomy in combination with otherobesity procedure (e.g., antrectomy, gastroplasty and biliopancreaticbypass) improves weight loss procedures. Tzu-Ming, et al., “Long-TermResults of Duodenectomy with Highly Selective Vagotomy in the Treatmentof complicated Duodenal Ulcers”, Amer. J. of Surg., Vol. 181, pp.372-376 (2001), Kral, et al., “Gastroplasty for Obesity: Long-TermWeight Loss Improved by Vagotomy”, World J. Surg., Vol. 17, pp. 75-79(1993), and Biron, et al., “Clinical Experience with BiliopancreaticBypass and Gastrectomy or Selective Vagotomy for Morbid Obesity”,Canadian J. of Surg., Vol. 29, No. 6, pp. 408-410 (1986).

[0154] Vagal neural blocking simulates a vagotomy but, unlike avagotomy, is reversible and controllable. Therefore, while obesity isparticularly described as a preferred treatment, the vagal neural blockof the present invention can be used as a less drastic procedure fortreatments previously performed with a vagotomy. Without limitation,these include obesity, ulcers or chronic pain or discomfort (alone or incombination with conjunctive procedures).

[0155] Further, bulimia has been identified as a disease amenable totreatment by decreasing afferent vagal activity via pharmacologicalvagal inhibitors delivered systemically. Faris, et al., “Effect ofDecreasing Afferent Vagal Activity with Ondansetron on Symptoms ofBulimia Nervosa: a Randomized, Double-Blind Trial”, The Lancet, pp.792-797 (2000). Therefore, bulimia and other diseases treatable withvagal blocker drugs can be treated with the targeted and site-specificvagal neural block of the present invention.

[0156] 3. Acute Treatment Device

[0157] a. Device Description

[0158]FIG. 12 illustrates a still further embodiment of the presentinvention where a nasogastric tube 300 is passed into the stomach. Itwill be appreciated that nasogastric tubes are well known and form nopart of this invention per se. Some nasogastric tubes have specializedfunctions. An example is a tamponade tube having gastric and esophagealballoons. An example of such is the Bard® Minnesota Four LumenEsophagogastric Tamponade Tube for the Control of Bleeding fromEsophageal Varices as described in product literature (information foruse) contained with the product of that name dated 1998 by C. R. Bard,Inc., Covington, Ga., USA. Further, while a nasogastric tube is apreferred embodiment other devices (e.g., an orogastric tube or anyelongated device to position electrodes near the esophagus/stomachjunction) could be used. Also, while placement at the esophagus/stomachjunction is preferred, the device can be placed in a different lumen(e.g., the trachea) for transmucosal stimulation.

[0159] The nasogastric tube 300 is multi-lumen tube which includesdistal openings 302 to which suction can be applied to remove gastriccontents through the tube 300. A compliant balloon 304 surrounds thegastric tube. Proximal to the balloon 304 is an opening 309 incommunication with a lumen (not shown) to which a suction can be appliedto remove saliva through the opening 309.

[0160] The balloon 304 has a plurality of electrodes which may includean upper array 306 of electrodes and a lower array 307 of stimulationelectrodes. The electrodes of the upper array 306 may be connected to ablocking signal source via conductors 306 a (FIG. 13). The electrodes ofthe lower array 307 may be connected to a stimulation signal source viaconductors 307 a. The conductors 306 a, 307 a may be passed through alumen in the tube 300 to an external controller (not shown). As aresult, multiple electrodes can be energized for transmucosalstimulation of the anterior and posterior vagus nerves AVN, PVN. FIG. 14shows an alternative design where the arrays 306, 307 are replaced withexpandable, circumferential electrodes 306′, 307′ connected to acontroller (not shown) by conductors 306 a′, 307 a′.

[0161] As in the embodiment of FIG. 10, the individual electrodes of thearrays 306, 307 may optionally be selectively energized to detect acardiovascular signal indicating an electrical coupling of theelectrodes to the vagus nerves AVN, PVN. Electrodes that do not createsuch a coupling may optionally be deactivated such that only theelectrodes having an effective coupling with the vagus nerves AVN, PVNwill be activated. Also, and as in the embodiment of FIG. 10, there maybe a single array of electrodes or all electrodes may be energized witheither a blocking or stimulation signal.

[0162] It will be noted in this embodiment that the electrodes aredisposed abutting the mucosal surface of the esophageal and stomachlining and are not in direct contact with the vagus nerves AVN, PVN.Instead, the electrodes are spaced from the vagus nerves AVN, PVN by thethickness of the stomach and lower esophageal wall thickness.

[0163] Transmucosal electrical stimulation of nerves is well known. Suchstimulation is disclosed in U.S. Pat. No. 6,532,388 to Hill et al datedMar. 11, 2003 (describing transmucosal stimulation of nerves across atrachea using a balloon with electrodes in the trachea to modulatecardiac activity). Also, the phenomena of transmucosal electricalstimulation of nerves is described in Accarino, et al, “SymptomaticResponses To Stimulation Of Sensory Pathways In The Jejunum”, Am. J.Physiol., Vol. 263, pp. G673-G677 (1992) (describing afferent pathwaysinducing perception selectively activated by transmucosal electricalnerve stimulation without disruption of intrinsic myoelectrical rhythm);Coffin, et al, “Somatic Stimulation Reduces Perception Of Gut DistentionIn Humans”, Gastroenterology, Vol. 107, pp. 1636-1642 (1994); Accarino,et al, “Selective Dysfunction Of Mechano Sensitive Intestinal AfferentsIn Irritable Bowel Syndrome”, Gastroenterology, Vol. 108, pp. 636-643(1994), Accarino, et al “Modification Of Small Bowel MechanosensitivityBy Intestinal Fat”, GUT, Vol. 48, pp. 690-695 (2001); Accarino, et al,“Gut Perception In Humans Is Modulated By Interacting Gut Stimuli”, Am.J. Physiol. Gastrointestinal Liver Physiol., Vol. 282, pp. G220-G225(2002) and Accarino, et al, “Attention And Distraction Colon Affects OnGut Perception”, Gastroenterology, Vol. 113, pp. 415-442 (1997).

[0164] Alternative embodiments of the transmucosal stimulation device ofFIG. 12 are shown in FIG. 15 and 16. In FIG. 15, the balloon 304′ isconical in shape with a base end 304 a′ placed distally on the tube300′. After expansion, the base end 304 a′ expands within the stomach S.The physician then pulls on the tube 300′. The base end 304 a′ (which islarger in diameter than the esophagus E) abuts the stomach S at thecardiac notch CN acting as a stop. This insures the electrodes 305′(only a single array is shown for ease of illustration) abuts themucosal tissue at the junction of the stomach S and esophagus E. Theelectrodes 305′ are on the narrow end 304 b′ of the balloon 304′ andexpansion of the balloon 304′ ensures contact of the electrodes with themucosal tissue.

[0165]FIG. 16 illustrates an embodiment using two balloons 304″ and309″. The distal balloon 309″, when expanded, is larger than theesophagus E and acts as a stop when the physician pulls on the tube300″. The electrodes 305″ are on a smaller balloon 304″ which may expandin the esophagus E. The balloon 304″, 309″ are positioned for theelectrodes 305″ to be against the mucosal tissue at the junction of thestomach S and esophagus E when the distal balloon 309″ abuts the cardiacnotch CN and the proximal balloon 304″ is expanded. The electrodes maybe positioned to be completely within the stomach to reduce risk ofinjury to esophageal tissue. More conveniently, a tube such as theafore-mentioned Bard® tube may be modified for electrodes to be placedon the proximal side of the gastric balloon.

[0166] In all of the foregoing, a balloon is expanded to urge theelectrodes against the mucosal tissue. While this is a presentlypreferred embodiment, any mechanism for urging the electrodes againstthe mucosal tissue may be used. In each of FIGS. 15 and 16, the tube300′, 300″ is shown as it passes through the balloons 304′, 304″ and309″. This illustration is made to indicate the tube passes through theballoons and does terminate at the balloons. In fact, as the tube 300′,300″ passes through the balloons 304′, 304″ and 309″ it would besurrounded by the material of the balloons 304′, 304″ and 309″ and wouldnot be visible.

[0167] A still further embodiment is shown in FIG. 17. Instead ofdirectly stimulating with current, the nerves are stimulated withmagnetic fields. In this case, the electrodes are coils 307′″ insulatedwithin the balloon 304′″. The coils 307′″ create magnetic fields whichinductively couple with the vagus nerves to create the blocking andstimulating impulses within the nerves.

[0168] b. Application to Acute Pancreatitis

[0169] When energized with a blocking frequency, the embodiment of FIG.13 is useful for treating acute or recurrent pancreatitis. Thisextremely serious disease is characterized by an over-active pancreaswhich excretes digestive enzymes to such an extent that the pancreasitself is digested. The disease can be extremely painful. In many cases,the disease is fatal. The number of US patients who suffer an episode ofacute pancreatitis is approximately 185,000 annually. Baron, et al.,“Acute Necrotizing Pancreatitis”, New England J. of Medicine, Vol. 340,No. 18, pp. 1412-1417 (1999). This high incidence, coupled with the costand length of stay required, make the total cost of this disease tosociety enormous. No definitive therapy is currently available to treatthese patients except supportive care. Furthermore, the overallmortality rate for severe pancreatitis is about 20 to 30%. Id.

[0170] A recent study reported that the average total hospital cost toobtain a survivor of severe, acute pancreatitis is nearly $130,000 withan average length of hospital stay of 40 days. Soran, et al., “Outcomeand quality of life of patients with acute pancreatitis requiringintensive care”, J. Surg. Res., 91(1), pp. 89-94 (2000). Furthercomplicating the management of these patients is the uncertaintysurrounding the prognosis because the course of the disease isunpredictable at initial presentation. Chatzicostas, et al., “Balthazarcomputed tomography severity index is superior to Ranson criteria andAPACHE II and II scoring systems in predicting acute pancreatitisoutcome”, J. Clinical Gastroenterology, 36(3), pp. 253-260 (2003). Ifpatients could be successfully treated during the initial phases of thedisease, with a higher survival rate, there is a high probability ofreturning to a productive life. Soran, et al., supra.

[0171] Pancreatitis may be associated with a number of etiologiesincluding chronic alcoholism or gallstones (e.g., gallstones lodged inthe pancreatic or common duct). When acute pancreatitis becomes severe,treatment options are severely limited. Morbidity and mortality ratesfor pancreatitis are sobering. Baron, et al., “Acute NecrotizingPancreatitis”, New England J. of Medicine, Vol. 340, No. 18, pp.1412-1417 (1999) and Steer et al., “Chronic Pancreatitis”, New EnglandJ. of Medicine, pp. 1482-1490 (1995).

[0172] Down-regulating vagal activity can be used to treat pancreatitis.A recently reported finding in experimental pancreatitis demonstratedthat the vagus nerves are strongly implicated in the pathophysiology ofpancreatitis. Yoshinaga, et al., “Cholecystokinin Acts as an EssentialFactor in the Exacerbation of Pancreatic Bile Duct Ligation-Induced RatPancreatitis Model Under Non-Fasting Condition”, Japanese J. Pharmacol,Vol. 84, pp. 44-50 (2000). Pharmacologic means of decreasing pancreaticsecretion have been attempted with limited success because of thedose-limiting side effects encountered with the drugs, their lack ofspecificity or their lack of availability. In fact, one recent trial ofa specific blocker of parasympathetic (vagus nerves) control ofsecretion demonstrated a shortened recovery period in patients withacute pancreatitis while trials with other pancreatic down-regulatingdrugs that are less specific or potent have proven to be disappointing.Zapater, et al., “Do Muscarinic Receptors Play a Role in AcutePancreatitis?”, Clin. Drug Invest., 20(6), pp. 401-408 (2000); Norton,et al., “Optimizing Outcomes in Acute Pancreatitis”, Drugs, 61(11), pp.1581-1591 (2001). Atropine is a drug that blocks parasympathetic nerveendings. It is known to be desirable to use atropine in acutepancreatitis patients to down-regulate pancreatic activity.Unfortunately, for most such patients, this drug cannot be used due toits many side effects.

[0173] Acute pancreatitis patients may be placed on intravenous feedingwith the device 300 left in place for a chronic length of time (e.g.,several days or weeks). At least the electrodes of the lower array 307may be energized with a blocking signal for the treatment of acutepancreatitis. The invention permits down-regulation of pancreatic outputthrough vagal blocking without the need for undesirable surgery fordirect vagal access.

[0174] In addition to utility for treating pancreatitis, the presentinvention may be used to avoid pancreatitis in patients having anincreased likelihood of developing the disease. For example, patientsundergoing endoscopic retrograde cholangiopancreatography (ERCP) and/orrelated procedures are known to having a higher likelihood of developingpancreatitis. Such patients may be treated with the present inventionwith a blocking signal to down-regulate pancreatic output and reduce thelikelihood of developing pancreatitis.

[0175] Many physicians treating patients with pancreatitis use anasogastric tube as part of the treatment. As a result, the presentinvention is illustrated as being incorporated on a nasogastric tube.However, a significant body of physicians adheres to a belief thatpancreatitis patients benefit from a feeding involving placingnourishment directly into the jejunum portion of the small intestine viaa naso-jejunal tube. While the present invention is illustrated in anembodiment of placement of the balloon and electrodes on a naso-gastrictube, the invention can also be placed on a nasojejunal tube or anasogastricjejunal tube.

[0176] c. Application to Ileus

[0177] With the device of FIGS. 12-16, the distal electrodes 307 may beenergized with a stimulation frequency as described for treatment ofileus. Post-trauma and post-surgery, patients may experience ileus whichis a dysfunction of the GI tract characterized in part by a lack ofmotility through the intestines. Prolonged ileus can result in stasisand serious infection. Kaiser, “Gallstone Ileus”, New England J. ofMedicine, Vol. 336, No. 12, pp. 879-880 (1997) (correspondence),Taguchi, et al., “Selective Postoperative Inhibition of GastrointestinalOpioid Receptors”, New England J. of Medicine, Vol. 345, No. 13, pp.935-940 (2001) and Steinbrook, “An Opioid Antagonist For PostoperativeIleus”, New England J. of Medicine, Vol. 345, No. 13, pp. 988-989 (2001)(Editorial).

[0178] Ileus patients commonly have nasogastric tubes as a regular partof their hospital stay. Without additional invasiveness, the presentinvention can be used as the nasogastric tube with the addition ofstimulation electrodes to stimulate the vagus to enhance motility.

[0179] The embodiment of FIG. 12 would permit the lower electrodes 307to be energized for stimulation frequency to treat ileus. Optionally,the upper electrodes 306 can be energized for blocking frequency ifneeded to prevent antidromic inhibitory responses or to preventundesired cardiac response.

[0180] The embodiment of FIG. 12-16 is useful to permit a diagnosis fora surgical implants as described in foregoing embodiments. Namely,responsiveness of a patient's gastrointestinal symptoms (such as IBS) tothe embodiment of FIG. 12 could justify a more invasive surgicalplacement of electrodes directly on the anterior or posterior vagusnerves.

[0181] In FIG. 15, a blocking or stimulating signal can be applied tothe electrode 305′. A blocking frequency is anticipated to be atherapeutic value for treating, for example, acute pancreatitis or anexacerbation of chronic pancreatitis. A stimulating frequency isanticipated to be of therapeutic value for treating ileus. With theembodiment of FIG. 12, ileus, for example, can be treated by applying astimulation frequency to the lower electrode 307. A blocking frequencyto the upper electrode 306 can be used to block antidromic responses orto block adverse side effects of the stimulation signal on proximalorgans (e.g., cardiac responses).

[0182] 4. Diagnostic Device

[0183]FIG. 18 illustrates a still further embodiment of the presentinvention where a stimulating electrode 400 is placed near a distal endof an esophageal gastric duodenal (EGD) scope 402. Leads (not shown)pass through the scope 402 connecting the electrode 400 to a controller(not shown).

[0184] Stimulation may be applied via the electrode 400 for transmucosalstimulation of an opposing vagus nerve (AVN in FIG. 18). Properplacement to achieve stimulation can be identified through thepreviously described techniques of identifying a cardiovascular responseto the stimulation indicating appropriate opposition of the electrode400 to a vagus nerve.

[0185] The scope may be left in place or may be removed by placing theelectrode attached to the mucosal wall (FIG. 19) through a pigtail orother attachment (such as an adhesive) with leads passing through thenostril or mouth. Alternatively, the electrode 400 may be kept in placepositioned underneath the mucosal layer and may be energized by radiofrequencies applied externally.

[0186] It will be appreciated that attachment of electrical apparatus tointernal mucosal layers of patients' is well known. Such a system isdescribed with respect to the Bravo™ pH monitoring system of Medtronic,Inc., Minneapolis, Minn., USA and as described in its product literatureUC 200300235 EN N15344 (2002) titled “Bravo™ pH Monitoring SystemCatheter-Free pH Testing”.

[0187] The foregoing embodiment is particularly useful for identifyingpatients responsive to blocking and stimulation as a diagnostic beforeapplying a more invasive procedure using the blocking and stimulationapparatus and methods described herein.

[0188] With the foregoing detailed description of the present invention,it has been shown how the objects of the invention have been attained ina preferred manner. Modifications and equivalents of disclosed conceptssuch as those which might readily occur to one skilled in the art, areintended to be included in the scope of the claims which are appendedhereto.

We claim:
 1. A method for treating at least one of a plurality of disorders of a patient where the disorders are characterized at least in part by vagal activity innervating at least one of a plurality of alimentary tract organs of said patient at an innervation site, said method comprising: positioning a neurostimulator carrier within a body lumen of said patient and with an electrode disposed on said carrier and positioned at a mucosal layer of said lumen in a region of a vagal trunk; applying an electrical signal to said stimulator to modulate vagal activity by an amount selected to treat said disorder.
 2. A method according to claim 1 wherein said electrical signal is applied at a frequency selected for said signal to create a neural conduction block to a vagus nerve of said patient at a blocking site proximal to said innervation site with said neural conduction block selected to at least partially block nerve impulses on said vagus nerve at said blocking site.
 3. A method according to claim 2 wherein application of said neural conduction block is variable by a controller to alter a characteristic of said block.
 4. A method according to claim 2 wherein said at least one of a plurality of disorders is pancreatitis.
 5. A method according to claim 4 wherein said neural conduction block is regulated to reduce a pancreatic output of said patient.
 6. A method according to claim 2 wherein said at least one of a plurality of disorders is obesity.
 7. A method according to claim 6 wherein said neural conduction block is regulated to heighten a sensation of satiety of said patient.
 8. A method according to claim 2 wherein said at least one of a plurality of disorders is constipation.
 9. A method according to claim 2 wherein said at least one of a plurality of disorders is irritable bowel syndrome or inflammatory bowel disease.
 10. A method according to claim 2 wherein said at least one of a plurality of disorders is vagally mediated pain.
 11. A method according to claim 2 wherein said at least one of a plurality of disorders is bulimia.
 12. A method according to claim 2 wherein said at least one of a plurality of disorders is ulcers.
 13. A method according to claim 1 wherein said lumen is a trachea of said patient.
 14. A method according to claim 1 wherein said lumen is an esophagus of said patient.
 15. A method according to claim 1 wherein said lumen is an interior of a stomach of said patient.
 16. A method according to claim 1 wherein said electrical signal is applied at a frequency selected for said signal to create a stimulation with an up-regulation of a vagus nerve of said patient at a stimulation site proximal to said innervation site.
 17. A method according to claim 16 wherein said at least one of a plurality of disorders is ileus.
 18. An apparatus for treating at least one of a plurality of disorders of a patient where the disorders are characterized at least in part by vagal activity innervating at least one of a plurality of alimentary tract organs of said patient at an innervation site, said apparatus comprising: a neurostimulator carrier sized to be passed through a selected body lumen of said patient and having an electrode disposed on said carrier to be positioned at a mucosal layer of said lumen; a source of electrical signal electrically coupled to said electrode to modulate vagal activity by an amount selected to treat said disorder.
 19. An apparatus according to claim 18 wherein said source is selected to generate a blocking signal selected to at least partially block nerve impulses on said vagus nerve at said blocking site.
 20. An apparatus according to claim 19 comprising a controller for selectively controlling parameters of said blocking signal.
 21. An apparatus according to claim 20 wherein said controller is inductively coupled to said electrode to electrically control said electrode remote from an interior of said patient's body.
 22. An apparatus according to claim 18 wherein said carrier is sized to pass into a trachea of said patient.
 23. An apparatus according to claim 18 wherein said carrier is sized to pass into an esophagus of said patient.
 24. An apparatus according to claim 18 wherein said carrier is sized to pass into an interior of a stomach of said patient. 